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For people who inherit any dominant mutation that causes Alzheimer’s disease, the question is not whether they will develop AD, but when. Now, a meta-analysis that drew both from several large cohorts and from the literature on such families reports that the two best prognosticators of onset are parental age at onset, and the type of mutation. The study was co-authored by 25 clinicians around the world and led by Randall Bateman of Washington University in St. Louis. The study also revealed that age at onset still varies even after controlling for these two parameters, and that ApoE genotype accounted for only a small part of this variability. The researchers suspect a combination of genetic and environmental factors are at play and call for more research to characterize those factors. The findings, published June 13 in Neurology, could help researchers refine their enrollment strategy for primary prevention trials in this population, which need to begin before symptoms emerge.

“These findings have clear implications for prediction of age at onset for clinical research,” John Kauwe of Brigham Young University in Provo, Utah, wrote in an email to Alzforum. Kauwe, who was not involved in the work, added that the study also reiterates previous findings showing a broad range of age at onset within familial AD (see full comment below).

Patterns in the Chaos. People with dominant mutations that cause Alzheimer’s disease succumb to symptoms at widely different ages, but some trends emerge when people are stratified by mutated gene. PS1 carriers tend to develop disease earlier in life than others, while those with PS2 mutations stay dementia-free longer. (Courtesy of Ryman et al., Neurology, June 13, 2014)

Researchers have so far identified 230 familial AD (FAD) mutations within the genes encoding for amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) (see Alzforum Mutations database). While most people who carry one of these mutations develop AD earlier than do people with the more common sporadic form of the disease, the variation in age at onset in FAD is large. Even among people who harbor the same disease-causing mutation it can be 40 years (see Larner et al., 2006). Improving the ability to predict a given person’s age at onset would help researchers select candidates for AD prevention studies who are most likely to show a benefit within the study’s duration.

The Dominantly Inherited Alzheimer’s Network (DIAN) treatment trial is testing the efficacy of the two AD immunotherapies solanezumab and gantenerumab (see Oct 2012 news story). In this trial, enrollees must be between 15 years younger and 10 years older than their parent’s age at onset. “This seemed to be a reasonable way to predict the age at onset, but it had never been investigated thoroughly,” first author Davis Ryman of Washington University in St. Louis told Alzforum. Ryman and colleagues set out to assess the predictive power of parental age at onset, and also to investigate whether other factors, such mutation type, might narrow those predictions to a smaller window.

They identified 137 published studies on familial AD that included information about causative mutations as well as parental age at onset. Three large international cohorts supplemented the dataset: the DIAN study, a large Colombian family cohort who share the same PS1 mutation (see Mar 2011 news story), and families who share the Volga German PS2 mutation (see Bird et al., 1988). When put together, the meta-analysis considered 387 families containing 3,275 people, of whom 1,307 developed AD at a known age.

The researchers found that people with familial AD started showing signs of cognitive decline at an average age of 46.2 years, as compared to the average of 68 years for late-onset AD. When stratified by gene, people with a mutation in PS1 tended to develop cognitive symptoms earlier than those with mutations in PS2 or APP, or people with APP duplication. However, huge variability existed throughout the FAD dataset. For example, among people with mutations in PS1, the age of onset ranged from mid-20s to mid-60s.

Mutation carriers of a given family tend to have a tighter spread in age at onset, but variability exists between carriers of the same mutation across different families, indicating that other environmental or genetic factors play a part in hastening or slowing the onset of disease.

The researchers confirmed that a carrier’s age at onset correlates with their affected parent’s age at onset, and more so with the average age at onset of their other affected relatives. However, the mutated gene was an even stronger predictor of onset age.

What explains the differences? Previous studies reported that the ApoE4 allele slightly hastens disease onset among people with the same dominant mutation (see Pastor et al., 2003, and Wijsman et al., 2005). Ryman and colleagues found that the ApoE genotype did affect age at onset of a given mutation in the predicted way—making it progressively younger going from E2E3 to E3E3 to E2E4 to E3E4 to E4D4. However, the total span of ApoE genotypes covered only a mean of three years age-of-onset difference and did not account for the variance in onset age within groups of people harboring a given FAD mutation. Ryman attributed this to the great strength of the causal mutations compared to the more subtle, modifying effect of ApoE genotype.

Given that each mutation may have somewhat different consequences on gene expression and/or function, Ryman was not surprised by the variability among groups sharing the same mutated gene. He told Alzforum the results showing some correlation between parental age at onset as well as the mutated gene were encouraging. “Either of these factors can explain a substantial amount of the variance,” he said. “But we also have to recognize that there is still a lot of variability between individuals, and the factors that cause it remain to be identified.”

Lindsay Farrer of Boston University, who was not involved in the study, called the meta-analysis authoritative. He said the findings confirmed what many have observed in much smaller samples. Farrer added that to determine the additional genetic factors that raise or lower age at onset, researchers will need to examine genetic associations within families carrying the same dominant mutation who live in a similar environment. To that end, researchers are sifting through genetic data from the Colombian kindred, which shares the E280A PS1 mutation, Farrer said.

Many members of the Colombian families included in this study are participating in the Alzheimer’s Prevention Initiative (API), which is testing the efficacy of crenezumab to stave off AD onset (see May 2012 news story and Nov 2012 news story). The average age at onset of this mutation is 38, albeit with significant variability, according to Ryman’s analysis. Participants in that trial start treatment at age 30 or older.

Ryman hopes the added results will allow researchers to better estimate a person’s age at onset in prevention trials and biomarker studies. Even so, the remaining variability precludes making strong predictions, he said. “Using the average age at onset of the mutation type seems to perform even somewhat better than parental age of onset in pinpointing where people are in the disease course,” Ryman said. “Perhaps this additional data can add some further precision.”—Jessica Shugart

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As the authors clearly articulate, these findings have clear implications for prediction of age at onset for clinical research. In addition, these results reiterate previous reports that autosomal dominant mutations have a broad range of onset, even well into the over-65-year range often associated with sporadic AD. Finally, this report strongly suggests that gene-gene and possibly gene-environment interactions that are shared within families have a significant influence on age at onset of autosomal dominant Alzheimer’s disease.